Throughout this application, various references are cited in parentheses to describe more fully the state of the art to which this invention pertains. Full bibliographic information for each citation is found at the end of the specification, immediately preceding the claims. The disclosure of these references are hereby incorporated by reference into the present disclosure in their entirety.
Abnormalities associated with inflammation comprise a large group of disorders which underly a variety of human diseases. The immune system is often involved with inflammatory disorders, demonstrated in both allergic reactions and some myopathies, with many immune system disorders resulting in abnormal inflammation. Non-immune diseases with aetiological origins in inflammatory processes are thought to include sepsis, cancer, atherosclerosis, and ischaemic heart disease.
A large variety of proteins are involved in inflammation, and altered expression and/or activity of one or more of these proteins can impair or otherwise dysregulate the normal immune function.
Vertebrates achieve internal homeostasis during infection or injury by balancing the activities of proinflammatory and anti-inflammatory pathways. However, in many disease conditions, this internal homeostasis becomes out of balance. For example, endotoxin (lipopolysaccharide, LPS) produced by all Gram-negative bacteria activates macrophages to release cytokines that are potentially lethal (Tracey, K. J. et al., Science, 234:470-74 (1986); Dinarello, C. A., FASEB J., 8: 1314-25 (1994); Wang, H., et al., Science, 285:248-51 (1999); Nathan, C. F., J. Clin. Invest., 79:319-26 (1987)).
Inflammatory disorders (such as septic shock caused by endotoxin exposure) are often induced by pro-inflammatory cytokines, such as tumor necrosis factor (TNF; also known as TNFα or cachectin), interleukin (IL)-Ia, IL-I β, IL-6, IL-8, IL-18, interferonγ, platelet-activating factor (PAF), macrophage migration inhibitory factor (MIF), and other compounds. Pro-inflammatory cytokines contribute to various disorders through their release during an inflammatory cytokine cascade.
Therefore, there is a need for a treatment for inflammatory disorders.